3-enol ethers of 6-formyl-3-oxo-delta4-steroids and process for their preparation



United States Patent 3,114,750 3 ENOL ETHERS OF 6 FORMYL 3 OXO-M- STEROIDS AND PROCESS FOR THEIR PREP- ARATION David Neville Kirk and Vladimir Petrow, both oi London, England, assignors to The British Drug Houses Limited No Drawing. Filed Nov. 6, 1961, Ser. No. 150,140 Claims priority, application Great Britain Nov. 7, 1960 33 Claims. ((11. 260-23955) This invention is for improvements in or relating to organic compounds and has particular reference to steriodal materials containing an additional carbon substituent at C It is an object of the present invention to provide a new and general process for the preparation of a new series of steroidal products which may be regarded structurally as the 3-enol ethers of 6 formyl-3-oxo-A -steroids.

We have made the surprising discovery that the 3-enolic ethers of 3-oXoA -steroids may be converted by the process of this invention into the corresponding 6-formyl derivatives. This is a discovery of outstanding importance in the field of steroid technology. Many of the herein described derivatives possess valuable biological properties which render them of value in, for example, the veterinary field. Thus, for example, the derivatives of 17,8-hydroxyandrostane which fall within the scope of the present invention may possess anabolic, androgenic and claudogenic properties. The derivatives of l7ot-acyloxypregnan-ZO-one tWillCh fall within the scope of the present invention may possess progestational properties when administered by the oral route. The derivatives of 16a,l7a-isopropylidenedioxypregnan-20 one may likewise show progestational activity as well as claudogenic activity. Claudogenic activity will, in general, also be shown by derivatives of 9a-fluoropregnan-l1,8,17a,21-trihydroXy- 20-one, 17a,21-dihydroXypregnane-l1,20-dione, 116,171, 21-trihydroxypregnane-20-one and by the Zl-acyl and 17,2l-diacyl derivatives thereof. In addition, such compounds may show glucocorticoid activity.

The compounds of the present invention form exceptionally convenient intermediates for the preparation of the therapeutically valuable Got-methyl steroidal hormones of the androstane and pregnane series, which compounds are now well-known in clinical practice, and into which they may be converted by reduction to 6-hydroxymethy1 derivatives, followed by treatment with H+ ions, when conversion into the corresponding 6-methylene-3-oXo-A steroids takes place. The last group of compounds, on catalytic hydrogenation followed by treatment with very dilute ethanolic hydrochloric acid or potassium hydroxide, yield the corresponding 6a-methyl-3-oxo-A -steroids. In addition the products of the present invention represent entirely new types of steroidal materials which themselves posses s intrinsic value as building blocks for other types of steroidal materials containing a C carbon substituent. Thus, for example, they may be expected to react with a variety of reagents such as the halogens, peracids, and to undergo hydrogenation. The numerous possibilities for reaction possessed by the products of the present invention will be apparent to those skilled in the art.

It is a further object of the present invention to provide 3,114,756 Patented Dec. 17, 1963 pharmaceutical preparations of the biologically active materials.

The present invention provides new 3-enol ethers of 6-formyl-3-oxo-A -steroids including the Formula ll below.

The invention also provides the following new products:

2l-acetoXy-6-formyl-l7tx-hydroxy-3-methoXypregna-3,5-

diene-l 1,20-dione 2 l -acetoxy- 1 lB-formoXy-6-formyl- 17 ot-hydroxy-3 methoxypregna-3,S-dien-ZO-one 2 l -acetoXy-1 1,B-hydroxy-6-formyl-17a-hydroXy-3- methoXypregna-3,S-dien-ZO-one 17a,2l-diacetoXy-6-formy1-3-methoxy-pregna-3,S-dien- 1 1,20-dione 2l-acetoXy-3-ethoxy-6-formyl-17u-hydroxypregna-3,5-

diene-1l,20-dione 21-acetoxy-6-formyl-17tt-hydroXy-3-(2'-hydroxyethoxy) pregna-3,5-dien-1 1,20-dione which are of value on account of their claudogenic activity.

170;,21-dihydroxy6-formyl-3-methoxypregna-3,S-diene- 11,20-dione, 17,2l-acetonide, and 17,21-orthoforrnate derivative 17a,21-dihydroxy-3-ethoXy-6-formylpregna-3,5-diene- 11,20-dione 17,20,20,2l-bismethylenedioxy derivative which are of value as intermediates for the preparation of the corresponding corticoid derivatives into which they may be converted by reduction to 6-hydroxyrnethyl derivatives, treatment with H+ ions, catalytic hydrogenation and acid hydrolysis.

21-acetoXy 17a-hydroXy-3-methoxy-6-formylpregna- 3,5 ,9( l1)-trien-20-one 21-acetoxy-6-formyl-3 -methoxypregna-3,5, 17 (20 trien-l l-one which are of value as intermediates for the preparation of the corresponding corticoidal types into which they may be converted as described above or by methods of prior art.

17a-acetoXy-21-fluoro-6-formyl-3-methoxypregna-3,5-

dien-ZO-one l7ct-acetoXy-6-formy1-3-methoXy-16a-methylpregna- 3 ,5 -dien-20-one 17a-acetoxyl 6-ethylidene-6-formyl-3-methoxypregna- 3, 5-dien-20-one l7wacetoxy-6-formyl-3-methoXy-l6-methylenepregna- 3 ,5 -dien-2 O-one 17a-acetoxy-6-formyl-3-rnethoxypregna-3,S-dien-ZO-one which are of value on account of their progestational properties upon oral administration.

6-formyl-3 methoxy :,1704 cyclomethylenepregna- 3,5 -dien-20 one which is of value on account of its claudogenie properties.

2 l-b enzylidene- 3 -ethoXy-6-formy1- l 6 cc, 1 7 OL-lS op ropylidenedioxypregna-3 ,S-dien-ZO-one 3-ethoXy-6-formyl16a,17a-isopropylidenedioxypregna- 3,5-dien-20-one which are of value on account of their claudogenic activwhich are of value on account of their anabolic and androgenic properties.

The 6-formyl-3-enolmethyl ether of testololactone which is of value in the experimental study of animal tumours.

1 1a, 17fl-diacetoxy-6-formyl-3-methoXyandrosta-3 ,5 -diene 6-formyl-3 -methoxyandrosta-3,5-dien-17-one 6-formyl-3-benzyloxyandrosta-3,5 -dien- 17 -one 17u-chlorethynyl-17fi-formoxy-6-formyl-3 -methoxyandrosta-3,5-diene 17 B-acetoxy-6-formyl-3-methoxy- 1 7u-methylandrosta- 3,5-diene which are of value as intermediates for the preparation of the corresponding 6-methylene and 6-methyl-3-oXo-A steroids into which they may be converted by the methods described above or by the application of methods of prior art.

3-ethoxy-6-formylspirosta-3,S-diene 6-formyl-3 -methoxy-16-lmethylpregna-3 ,5, 16-trien-20-one 6 formyl-l7u-hydroxy-3-methoxy-l6-methylenepregna- 3,5-dien-20-one 3-ethoxy-6-formylpregna-3,5,17(20) trien-21-oic acid ethyl ester 1 a-acetoxy-6-formyl-3-methoxypre gna-3 ,5 -dien-20-one 16m-cyano-6-formyl-3-methoxypregna-3,5-dien-20-one 16a,17oc-epoxy-6-formyl-3-methoxypregna-3,5-dien-20- one which are of value as novel intermediates for the preparation of 6-methylene and 6-methyl-3-oxo-A -steroids.

21-aoetoXy-3-ethoxy-6-formylpregna-3,5dien-20-one 21-acetoxy-3-methoXy-6-formylpregna-3,5-dien-20-one 6-formyl-3-methoxypregna-3,5-dien-20-one which are of value on account of their claudogenic activity.

fi-[3-ethoxy-6-formyl-175-hydroxyandrosta 3,5 dien- 17a-yl] propionic acid lactone which is of value as an intermediate in the preparation of the corresponding 60cmethyl-3-oxo-A -'derivative of prior art into which it may be converted by the methods hereinbefore described or by the application of known procedures. The 6-methylated spirolactone is a potent aldosterone antagonist.

According to the present invention there is provided a process for the preparation of 3-enol others of 6-formyl- 3-oxo-A -steroids including the formula O HO where R O-alkyl, O-hydroxyalkyl, O-cycloalkyl, O-alkaryl or a functional derivative thereof which process comprises treating a corresponding 3-enol ether of a 3- oxo-A -steroid including the formula where R has the same meaning as above with a formylating agent which does not modify the conjugated system to yield the 6-formyl derivative.

The formylating agent which does not modify the con jugated system in order to yield the 6-formyl derivative is the Vilsmeier reagent (see for example Houben-Weyl, Methoden der Organische Chemie, 4th ed., 1954, vol. 7 (1), page 29 et seq., Bosshard and Zollinger, Helv. Chim. Acta, 1959, 42, 1659).

The invention also provides a process for the preparation of 6-forrnyl-3-oxo-A -steroids of the androstane and pregnane series including the formula Me Me (31111 11 134 (3 R8 o "-34 a= l R Me Me I R I R 3 R W) (V where R is CHO,

R is H or Me,

R is H, HOH or =0,

R is H, Me, OH or OAcyl (where the acyl group contains up to 10 carbon atoms),

R is H, R or F,

R is H, Me, Et, vinyl, ethynyl, propynyl, chlorethynyl or OH,

R is CH CHR C=CH C CHMe, CH.CH OH, CHCN or CHI-Ial where Hal is Cl, Br or F,

R and R together form O.CMe .O.CH- or R is :O, H(OH) or H(OAcyl),

R and R together form .O.CO.CH .CH or =0,

R represents part of an enol ether moiety, and the 9(1l)-dehydro derivatives thereof which process comprises treating the corresponding enolic 3-substituted 3,5- dienic steroid of the androstane or pregnane series with the Vilsmeier reagent followed by aqueous hydrolysis.

As known to those skilled in the art the condensation of an unsaturated system with the Vilsmeier reagent is generally carried out under essentially anhydrous conditions when an iminium intermediate is obtained, which passes into the required formyl derivative on aqueous hydrolysis. As hereinafter described, the Vilsmeier reagent for the purpose of the present invention is preferably a complex formed from a formamide (erg. dimethylforrnainide) and an acidic reagent such as phosphorus oxychloride or phosgene. The reaction is preferably carried out at room temperature or below for example at approximately 0 C.

The Vilsmeier reagent is used by those skilled in the art for introducing the aldehyde group into aromatic, quasiaromatic and certain heterocyclic ring systems. Its application to the steroid field has not hitherto been reported. Its present application to the enolic derivatives of 3-oxo-A -steroids represents an important, highly specific and unexpected development of the art as the corresponding 3-enol acetates of 3-0Xo-A -steroids, as Well as 3-ethoxy-A -steroids and 3-oxo-M-steroids all fail to yield 6-formyl derivatives under the conditions of the present invention.

A particularly surprising feature of the present invention is the successful utilisation of 3-enolic ethers as such 3enolic ethers are known to be highly unstable in the presence of acidic reagents.

Another suipn'sing feature of the invention is the stability of the resulting 6-formyl 3-enol-ic derivatives which could not have been predicted by prior art and represents a vital factor in the success of the process of the present invention. Inter alia We have made the stirprising discovery that the product (II) of the present invention can undergo ether interchange on prolonged heating with alcohols ROH in which R' has a lower molecular weight than R. Thus, for example, 3-ethoxy-6fiormyl- A -derivatives (II; R =EtO), on prolonged boiling with methanol undergo ether interchange to yield the corresponding 3-methoxy-6-formyLA -derivatives Enolic ethers [(1) where R is O-alkyl, O-hydroxy alkyl, O-cycloalkyl or O-ialkaryl, as well as chemical equivalents thereof such as :chloroalkyl or alkoxvalkyl] may be employed as starting materials for the invention. Methyl-, ethyland benzyl-ethers (in which R is MeO, EtO and B20) form the preferred group of starting materials and may be readily prepared from 3-oxo-A -steroids by methods Well-established by prior art. 'O-hydroxyalkyl-enol ethers (in which R is HO.CH .(CH ),,O) may also be employed and may be prepared in situ from the corresponding 3,3-alkvlenedioxy-A -derivatives and chemical equivalents thereof in the presence of the Vilsmeier rea gent with which they subsequently react to yield the 6- formyl derivatives of the corresponding 2-hydroxyethyl enol ethers.

Vilsmeier reagent.The Vilsmeier reagent is generally understood to be a reactant formed from a formylated secondary amine and an acid halide selected from the group comprising those acid halides which readily undergo nuoleophilic displacement of a halide ion on treatment with the N formyil derivative of a secondary amine [see, for example, Bosshard and Zollinger, Helv. Chim. Acta, 1959,, 42, 1659].

Various formamides such as Dimethylformamide Diethylformamide Methylphenylformamide Ethylphenylfiormamide Formylpiperidine Formylmorph-oline Methylethylformamide may be employed. As mentioned above dimethylformamide is the preferred formamide.

In addition to phosphorus oxychloride and phosgene, other acidic reagents such as phosphorus oxybromide and pentachloride may be employed. Thionyl chloride, oxalyl chloride and similar acid halides may also be used. Phosgene is the preferred reagent,

Preferred procedure for preparing o-formyl derivatives.Phosgene (generally about one mole) either directly or in solution in an anhydrous nonhydroxylic organic solvent, which is preferably a halogenated hydrocarbon solvent such as methylene dichloride, chloroform, carbon tetrachloride or ethylene dichloride, is added at 0 C., to a solution of dimethylformamide, preferably in one of the foregoing chlorinated hydrocarbon solvents, when formation of the Vilsmeier reagent occurs. It is preferable at this stage to obtain a reagent free from excess phosgene by ensuring the presence of not less than an equivalent quantity of dimethylformamide and to prepare it under essentially anhydrous conditions. Other organic solvents which can be employed include dioxan,

tetrahydrofuran, ether, benzene, toluene, ethyl acetate and triiluorotrichloroethane.

Dimethylfo-rmamide can also be used as both solvent and reactant.

The stereoidal enol ether, either in solution (preferably in one .of the foregoing halogenated sol-vents) or in the finely-powdered state, is then added at. preferably 0 C., to the prepared Vilsmeier reagent. The mixture is preferably stirred, moisture is excluded, and the reaction allowed to proceed spontaneously, when darkening of the solution occurs and the temperature of the mixture rises. In general, in working with small batches of material, external cooling is not necessary, but such cooling may become desirable when the scale of the reaction is increased. Reaction is generally complete in 1 to 2 hours. The resulting iininium salt is then decomposed by aqueous hydrolysis and the 6-formyl deriv-ative isolated by extraction or filtration. As will be apparent to those skilled in the art :a buffered solution such as aqueous sodium acetate or aqueous methanolic sodium acetate is entirely satisfactory for effecting hydrolysis of the iminium intermediate. Hydrolysis of the iminium. intermediate is accompanied by formation of acidic materials (e.g. HCl) which, unless removed by a base or buffer in situ, could react with acid-sensitive groups such as the corticoid side-chains if present in the steroidal materials thereby lowering the yields of 6-formylated products. The use of buttered aqueous solutions for decomposing the iminium intermediates is, of course, unnecessary when steroid materials containing substituents stable to acids are employed. For such materials, water or aqueous acetic acid may be used in place of buffered aqueous solutions so desired.

In general, ca. 1.l1.3 molar proportions of Vilsmeier reagent are sutficient in those cases in which the Vilsmeier reagent is Wholly utilised for 6-formy1ation. As will be apparent to those skilled in the art the quantity of Vilsmeier reagent will, in general, have to be increased in those cases or experimental situations in which reactions other than o-formylation take precedence over or compete with 6-formylation. Thus, for example, as indicated ereinunder, primary, secondary and certain tertiary hydroxyl groups are converted into formoxy groups by the Vilsmeier reagent unless protected for example by acylation or etherification. In general, conversion of such reactive hydroxyl groups into formoxy groups competes with and takes precedence over 6formylation. Thus reaction of the 3-enolether of testosterone with ca. 1 molar proportion of Vilsmeier reagent leads primarily to the production of the l7-formate. Reaction of the same 3-enol ether of testosterone with ca. 2.5 molar equivalents of Vilsmeier reagent, in contrast, leads to the formation of the 6-'"ormyl derivative of the 17-formate. As primary and secondary formoxy groups, as known by prior art, are very readily hydrolysed, it is possible to effect hydrolysis of the 17-formate residue during the process of isolation of the 6-formyl derivative as described in EX- ample 26. Cortisone 21- acetate enol ethers and similar structures give excellent yields of 6-formyl derivative when treated with ca. 1.6 moles of Vilsmeier reagent. 16a,17ot-epoxy groups likewise react with the Vilsmeier reagent (see below) and this point should also be taken into account by those skilled in the art.

Scope of the o-formylation reaeti0n.-The 6-formylation reaction is generally applicable to the enolic derivatives of S-oxo-M-steroids. Thus, for example, it may be successfully applied to derivatives of androstane including androstane, 19-norandrostane, 9,8,10wandrostane and more complex derivatives thereof such as cholestane, spirostane, ergostane and stigmastane. Again the 6-formylation reaction may be applied to derivatives of pregnane including pregnane, l9-norpregnane and 95,10otpregnane. Such systems may additionally contain further substituents as indicated below:

H ydroxyl groups. The Vilsmeier reagent is known by prior art to formylate or replace by halogen free hydroxyl groups (see Houben-Weyl, loc. cit). It may be advantageous, therefore, to protect hydroxyl groups by acylation and subsequently regenerate them by hydrolysis or hydrogenolysis if so desired. As formate esters are readily hydrolysed, however, such formylation as may occur during the Vilsmeier reaction, may be reversed by hydrolysis of the formed formats ester.

Thus, in Example 26 is described the 6-formylation of testosterone 3-methyl ether using 2.5 moles of Vilsmeier reagent to give by the process of the example, 6-formyl-3- methoxyandrosta-3,S-dien-17,8-01. Again, by treating the 3-enol ether of cortisone 21-acetate with ca. 1.6 molar proportions of the Vilsmeier reagent, a yield of the 6- formyl derivative which may exceed 80% is obtained without apparently any concomitant reaction of the unesterified 17ot-hydroxyl group taking place. The pseudoequatorially oriented tert. 17/3-hydroxy group in compounds such as 17a-methyl-, 17a-chloroethynyl and 17apropynyl testosterone will, in general, require acylation to prevent its formylation during the Vilsmeier reaction. Hydroxyl groups and functional derivatives thereof in such positions as 11, 12, 16 (including 16-hydroxy methyl), 14, l5, 17, 18, 19, 20 and 21 (including the condensation products of 16a,17u-glycols with carbonyl components), however, generally permit normal formylation at C to take place. Thiol groups at C are unalfected.

Carbonyl groups.Carbonyl groups such, for example, as carbonyl groups at 11, 12, 15, 16, 17, 18 and 20.

Carbalkoxy grups.Carbalkoxy groups at C C and C or in the side-chain. Cyano-groups at C C and C likewise permit normal C formylation to occur.

Alkyl groups.-Alkyl groups other than at C and C and in particular methyl groups at C C C C and C21 and at C17.

Alkenyl gr0ups.-Vinyl, allyl, alkynyl and chloroalkynyl as well as propynyl and chloroethynyl groups at C Methylene and ethylidene gr0ups.-At positions 11, 16 and 17.

Such groups as benzylidene, particularly benzylidene attached to C do not interfere with the process of the invention. The reaction may also be performed in the presence of 16,17-methylene.

Lactone, ether and spiroketal residnes.-Spirolactone residues such as O.CO.CH .CH attached to C etheric groups at C and bridging C and C20, spiroketal moieties such as are present in diosgenone, ketalised carbonyl groups for example at C or C Halogen gr0ups.-Chlorine, bromine or fluorine substituents in Rings C and D or in the sidechain do not interfere with the process of the invention. In particular the invention may be applied to 9oz, 16 and 21-fiuorosubstituted derivatives.

Unsaturated linkages-Unsaturated linkages at C 11 14 C16 and 17(20)- Ketol gr0ups.-Ketol groups at G -C C1q-C2 and C -C are preferably acylated or otherwise protected prior to reaction with the Vilsmeier reagent.

Corticoid side chain.The corticoid side chain may be protected by acylation at C or at C and C by reaction with formaldehyde to give the bismethylenedioxy derivative, by forming the C1'7C21 cyclic carbonate, acetonide or by other methods known to those skilled in the art, and subsequently regenerated as desired.

Epoxides. 16fl-methyl-16a,17ot-epoxypregnan-20-one derivatives may be converted in one operation into the corresponding 6-formyl derivatives of 17a-hydroxy-16- methylenepregnan-ZO-one by using approximately 2 molar proportions of the Vilsmeier reagent. 16a,17a-epoxypregnan-ZO-one residues are converted into l6fi-halo-17ahydroxypregnan-ZO-oue structures, but an excess of Vilsmeier reagent over that required by theory is required to force this reaction to completion. The epoxy-group may subsequently be regenerated from the crude halohydrin by reaction with an alkaline reagent such for example, as methanolic sodium hydroxide or by other methods wellestablished by prior art. The process of the invention may be performed in the presence of bromo, chloro and fiuorohydrins, particularly at C :C and C :C

The process of the invention may be used for the 6- formylation of 3-enol ethers (and acyl derivatives thereof) derived from the following steroidal 3-oxo-4-enes.

Testosterone 2-rnethyltestosterone 9 1 1 dehydro-17a-methyltestosterone 17a-propynyltestosterone 17a-acyloxyprogesterone 9 1 1 dehydro-17a-acyloxyprogesterone 16-methyl-17ct-acyloxyprogesterone 9 1 1 dehydro-l 6-1nethyl-17a-acyloxyprogesterone 16-methylene-17a-acyloxyprogesterone 9 1 l dehydro-16-methylene-17a-acyloxyprogesterone 17a-acyloxy-1-ethylideneprogesterone 16a,17a-dimethylmethylenedioxyprogesterone 9 1 1)dehydro-16a,17ot-dimethylmethylened ioxyprogesterone Cortisone 16-methylcortisone 2 l-methylcortisone lo-methylenecortisone 16a-hydroxy cortisone and the 16cc, 17cc acetonide thereof Hydrocortisone 16-metl1ylhydrocortisone 2 1-methylhydrocortisone 16methylenehydrocortisone 16ahydroxyhydrocortisone and the a, a) acetonide thereof 17u,21-dihydroxypregna-4,9(11)-diene-3 ,20-dione 16-methyl-170,21-dihydroxyp1'egna-4,9 1 1)-diene-3,20-

dione 21-methyl-17a,21-dihydr0xypregna-4,9(1 1 )-diene-3,20-

dione 16-methylene-17a,21-dihydroxypregna-4,9(1l)-diene-3 ZO-dione 16a-hydroxy-17ot-21-dihydroxypregna-4,9 1 1 diene- 3 ,ZO-dione and the (16,17)-acetonide thereof 2 l-fiuoro-17a-hydroxypregna-4,9 1 1)-diene-3 ,20-dione and the 16,17) acetonide thereof 2 l-fluoro-17a-l1ydroxypregn-4-ene-3, 1 1,20-trione and the (16, 17 acetonide thereof 21-fiuoro-1 1,17a-dihydroxypregn-4-ene-3 ,20-dione and the 16, 17 acetonide thereof 2 1-hydroxypregna-4, 17-dien-3-one 1 1-oxo-2 1-hydroxypregna-4, 17 ien-3 one 1 1,21-dihydroxypregna-4,17-dien-3-oue 9 11)dehydro-Z1-hydroxypregna-4,l7-d ien-3-one 3-oxopregna-4,17-dienoic acid (esters) 3, l 1-dioxopregna-4,17-dienoic acid (esters) 1 1-hydroxy-3-oxopregna-4,17-dienoic acid (esters) 9( 1 1)-dehydro-3 -oxopregna-4,17-dienoic acid (esters) 2 l-fluoro-17ot-acyloxyprogesterone Progesterone l-methylprogesterone 1 l-oxoprogesterone 9 1 1 dehydroprogesterone 21-metl1ylprogesterone Diosgenone 17a-cyano-17,8-hydroxyandrost-4-en-3one l6-methyl- 16, 17-dehydroprogesterone 16-cyano-progresterone 16-carbalkoxyprogesterone 1 6hydroxymethylprogesterone 3 -(3oxo-17fi-hydroxyandrost-4en-17ot-yl) propionic acid 21-fiuoroprogesterone Testololactone 16-fluoro-corticoids The 9a-fiuoro derivatives of the above 11,6-hydroxy and ll-oxo-steroids Following is a description by way of example of methods of carrying the invention into effect.

EXAMPLE 1 Preparation of 3 -E in wry-6 -F ormyl 6 a,] 7ot-Is0pr0pyli denedioxy pregna-3 ,5 -Di en-Z O-One EtO- ( JHO Sulphuric acid (4 drops: concentrated) in dioxan (8 ml.) was added to a suspension of 16a,17a-isopropylidene dioxypregn-4-ene-3,20-dione (Cooley, Ellis, Hartley and Petrow, J. Chem. Soc, 1955, 4373) (8.5 g.) in a mixture of dioxan (45 ml.) and ethyl orthoformate (9 ml.). Crystals began to separate after 15 minutes. After 30 minutes, pyridine (0.5 ml.) was added, followed by a large volume of water. The precipitate was crystallised from aqueous dioxan containing a trace of pyridine to give the enol ethyl ether, needles, M.P. 216 to 217 C., [M -64 (c., 1.0in chloroform).

A stirred mixture of dimethylformamide (11 ml.) and ethylenedichloride (40 ml.) at C. was treated with phosgene (7.5 g.) in ethylenedichloride (75 m1.) added dropwise over 30 minutes. Ten minutes later, a suspension of the foregoing enol ether (10 g.) in ethylenedichloride (50 ml.) was added, and the mixture stirred at room temperature for 2 hours. After hydrolysis with aqueous methanol-sodium acetate, the product was isolated with ether and purified from ethanol. 3 ethoxy-6- formyl 1 6ca,17oc isopropylidenedioxypregna 3,5 dien- -one separated in needles, M.P. 203 to 206 C., [001 -85 (c., 0.81)

EXAMPLE 2 Preparation of 21 -A cet0xy-3 -Methoxy-6-F0rmy [pregna- 3,5-Dien-20One C 11 0 Ac The 3-methyl enol ether of desoxycorticosterone acetate [10.5 g., M.P. 158 to 160 C., [111 15.2 (c., 0.92 in dioxan), prepared by treating desoxycorticosterone acetate with methyl orthoformate and a trace of concentrated sulphuric acid in dioxan] in dry ethylene dichloride (50 ml.) containing a trace of pyridine was added at 0 C. to a suspension of the complex prepared from dimethylformarnide (5.75 g.) and phosgene (3.9 g.) in dry ethylenedichloride (65 ml). The mixture was stirred and allowed to warm to room temperature over 2 /2 hours, after which time it was poured into a solution of sodium acetate (anhydrous, 15 g.) in methanol (100 ml.). After a further 10 minutes, water was added, the product was extracted into ether, the extract was washed with aqueous sodium carbonate and water, dried over anhydrous sodium sulphate, treated with charcoal and evaporated to dryness under reduced pressure. Crystallisation from aqueous methanol gave 21-acetoxy-3-methoxy-6-formylpregna-3,5-dien-20-one as needles, M.P. 128 to 130 C., [021 59.5 (c., 0.95 in chloroform), A 218.5 to 220 ma (2 10,280) and 319.5 to 321.5 m (6 15,420).

EXAMPLE 3 Preparation of 1 7a,20:20,21 -Bismethylenedioxy-3-Ethoxy- 6-F0rmylpregna-3,5-Dien-11- One OC H2 17a,20:20,21 bismethylenedioxy 3 ethoxypregna- 3,5-dien-1l-one [9.8 g., MP. 167 to 169 C., [od l37 (c., 0.63 in chloroform), prepared from bismethylenedioxy cortisone and ethyl orthoformate in the presence of a trace of concentrated sulphuric acid in dioxan] suspended in dry ethylenedichloride (50 ml.) containing a few drops of pyridine was added at 0 C. to a suspension of the complex prepared from dimethylformamide (4.38 ml.) and phosgene (3 g.) in dry ethylenedichloride (50 ml.). The mixture was stirred and allowed to warm to room temperature over 3 hours. 17a,20:20,21-bismethylenedioxy 3 ethoxy 6 formylpregna 3,5 dien 11- one was isolated as described in Example 2. It crysta lised from dichloromethane/methanol, MP. 212 to 215 C., 154 (c., 0.88 in CHCl A2,? 218 to 219 ma (6 11,280) and 321 ma (6 15,680)

EXAMPLE 4 Preparation of 3-Meth0xy-6-F0rmylpregna-3,5-Dien-20- One C OMe JHO The 3-rnethyl enol ether of progesterone [1 g., M.P. 158 to 160 C., M1 65 (0., 0.71 in dioxan) 7\,,,,,,; 240 nm (e 19,150) prepared from progesterone and methyl orthoformate in dioxan containing a trace of toluene-p-sulphonic acid], suspended in dry ethylenedichloride (5 ml.) containing a trace of pyridine, was added at 0 C. to a suuspension of the complex formed from dimethylforrnamide (1.4 ml.) in ethylenedichloride (4 ml.) and 10% w./v. phosgene/ethylenedichloride solution (7.5 ml.). The mixture was stirred and allowed to warm to room temperature over 2 hours. 3-rnethoxy- 6-formylprcgna-3,5-dien-20-one, 'y 1707, 1 668, 1618, 1584 cm? (in CH Cl was isolated as in Example 2.

EXAMPLE 5 Preparation of 3-Methoxy-6-Formylandrosta-3,5-Dien-17- One Phosgene (7.5 g.) in ethylenedichloride (75 ml.) was added dropwise, over 30 minutes, to a stirred mixture of dimethylformamide (11 ml.) and ethylenedichloride (40 ml.) maintained at C. After being stirred for a further 10 minutes, the mixture was treated with a solution of 3-methoxyar1drosta-3,5-dien-l7-one (M.P. 158 0, prepared from androst-4-ene-3,20-di0ne, and methyl orthoformate in dioxan containing a trace of toluene-p-sulphonic acid) (10 g.) in ethylenedichloride (50 ml.), and the whole stirred at room temperature for 1% hours. After hydrolysis with aqueous methanol/ sodium acetate, the product was isolated with ether to give 3-methoxy-6- formylandrosta-3,5-dien-17-one, needles (from aqueous methanol), M.P. 191 to 193 C., [a] --92 (0., 0.61 in chloroform), 'y 1750, 1650, 1610 and 1580 cm.

EXAMPLE 6 0A0 Me p EtO The 3-ethyl enol ether of Za-methyltestosterone acetate (6 g.) [M.P. 188 to 190 C., 121.9 (c., 0.64 in pyridine) prepared from 2oc-methyltestosterone acetate and ethyl orthoformate in dioxan, containing a trace of sulphuric acid] in dry ethylenedichloride (30 ml.) was added at 0 C. to a suspension of the complex formed from phosgene [3.4 g. in 34 ml. dry ethylenedichloride] and dimethylformamide (6.6 ml.) in ethylenedichloride (32 ml.). The mixture was stirred and allowed to come to room temperature over 3 hours, 17/3-acetoxy-3-ethoxy- 6-forrnyl-2a-methylandr0sta-3,5-diene, isolated as in Example 2, separated from aqueous methanol, M.P. 188 to 119 C., [M 123 (c., 1.28 in CHCl Concentrated sulphuric acid (4 drops) in Analar dioxan (8 ml.) was added to a suspension of diosgenone (8.5 g.) in Analar dioxan (45 m1.) and ethylorthoformate (9 mL). After one hour, pyridine (0.5 ml.) was added, and the solution poured into a large excess of water. The precipitate was crystallised from acetone, containing a trace of pyridine, to give the enol ethyl ether, long needles, M.P. 171 to 174 C.

A stirred mixture of dimethylformamide (1.1 ml.) and ethylenedichloride (4 ml.) at 0 C. was treated with phosgene (0.75 g.) in ethylenedichloride (7.5 ml.) added dropwise over /2 hour. Stirring was continued for 10 minutes, after which time a suspension of the foregoing enol ether (1 g.) in ethylenedichloride ml.) was added. The mixture was stirred at room temperature for hour.

After hydrolysis with aqueous methanol/sodium acetate, the product was isolated with ether to give 3-ethoxy-6- formyl-ZSD-spirosta-3,5-diene, 'y 1660, 1620, 1580 cmf EXAMPLE 8 Preparation of 1 700-14 cetoxy-6-Formyl-3-Meth0xy-1 6- Met/1ylenepregna-3,5-D iene-ZO-One C OMe CHO 17a-acetoxy-16-methylenepregn 4 ene 3,20 dione (Kirk, Petrow, Stansfield and Williamson, J. Chem. Soc., 1960, 2385) (3.3 g.) suspended in dioxan (18 ml.) containing methylorthoformate (3.6 ml.) was mixed with dioxan (3.2 ml.) containing 2 drops of concentrated sulphuric acid. On stirring, the steroid dissolved and after 5 minutes the product crystallised. Pyridine was added to the mixture which was poured into water and the precipitated solids were collected and crystallised from methanol containing pyridine to give 17a-acetoxy- 3-meth0xy 16 methylenepregna-3,5-dien-20-one as needles, M.P. 225 to 227 C., [Q 242 (c., 1.01 in chloroform),

15g 240.5 ma

To a solution of dimethylformamide (1.25 ml.) in ethylenedichloride (5 ml), cooled in an ice-bath was added dropwise 10 ml. of a 9.5% w./v. solution of phosgene in ethylenedichloride. The resulting white slurry was stirred for a further 10 minutes and then a suspension of 17a-acetoxy-3-methoxy-16-methylenepregna-3,S-dien- 20-one (3.4 g.) in ethylenedichloride (20 ml.) was added. The mixture was stirred and the temperature was allowed to rise. After 20 minutes, the reaction mixture was poured into a solution of sodium acetate (3 g.) in methanol (20 ml.) and water (5 m1.) and shaken well. The product was isolated with ether and purified from aqueous methanol to give l7a-acetoxy-6-formyl-3-methoxy-16- methylenepregna-S,5-dien-20-one, M.P. 203 to 205 C.,

A232? 220 m and 321 m EXAMPLE 9 Preparation of 6-F0rmyl-3-Meth0xy-16-Methylpregna- 3,5,16-Trien-20-One O 0 Me CI-IO Dimethylformamide (6.1 ml.) in ethylenedichloride (21 ml.) was cooled and stirred at C. and 40 ml. of a 10% w./v. solution of phosgene in ethylenedichloride added dropwise over 30 minutes. After 10 minutes further stirring, 5.53 g. of the foregoing enol ether in suspension in 50 ml. ethylenedichloride was added all at once. The mixture was stirred at room temperature for 4 hours, and left for 24 hours. The dark red solution was then poured into a solution of 8 g. potassium acetate, 15 ml. water and 60 ml. methanol, shaken, water added, and the whole ether-extracted. The combined extracts were washed with water, sodium bicarbonate, water, dried and evaporated.

The residual oil was percolatcd through a short column of alumina in benzene, and the yellow fractions combined and evaporated to give an oil which solidified on trituration with hexane. The solid was recrystallised from benzene/hexane to give the pure 6-formy1 derivative, MP. 76 to 80 C., 'y 1588, 1618, 1649 cmf x512? 322 m 14,115) and 244 111; (e 11,315)

EXAMPLE Preparation of I7/3-Acetoxy-6-FormyZ-S-Methoxyandr0sta-3,5-Diene MeO- ( DHO A solution of dimethylformamide (16 g.; 0.22 mol.) in ethylenedichloride (130 ml.; anhydrous) was cooled to 0 C. and stirred during dropwise addition of phosgene [11 g. (0.11 mol.) in 10% w./v. solution in ethylenedichloride] over /2 hour. A white precipitate formed. After an additional 10 minutes stirring, 17,8-acetoxy-3- methoxyandrosta-3,S-diene (34.4 g., 0.1 mol.) in ethylenedichloride (160 ml.) containing pyridine (0.1 ml.) was added all at once. The mixture was stirred and the temperature allowed to rise to room temperature. A deep red colour developed rapidly. The solution was stirred for 1 hour, during which the complex dissolved. The mixture was then poured into a solution of sodium acetate (25 g.; anhydrous) in water (25 ml.) and methanol (150 ml.), stirred 10 minutes, diluted with water, and the product was extracted with ether. The ether was washed with water and sodium bicarbonate solution, dried (sodium sulphate), stirred with charcoal, filtered and the solvents removed in vacuo. The residue was treated with a little acetone which was removed in vacuo to eliminate ethylenedichloride. The residue was purified from acetone/hexane, followed by methanol to give 17 ,8 acetoxy-6-formyl-3-methoxyandrosta-3,S-diene as blades, MP. 159 to 162 C.,

N 320 111g. (6 14,930) and 220 in, (6 10,240); 'y

(in CH Ch) 1726, 1651, 1616, and 1581 cmf 11 153 (0., 0.86 in dioxan) EXAMPLE 11 Preparation of 1 7,8-A cetoxy-fi-Formyl-SJlethoxyandrosta-3 ,5 -Di ene A solution of freshly distilled phosphorus oxychloride (20 g.) in anhydrous ethylenedichloride (80 ml.) was added dropwise to a stirred solution of dimethylformamide (20 ml.) in ethylenedichloride (80 ml.) which was cooled in ice. 17/3-acetoxy-3-methoxyandrosta-3,S-diene (20 g.) was added to the solution which was stirred and allowed to warm to room temperature over 2 hours. The

EXAMPLE 12 Preparation 0 I 7a-A cet0xy-6-F0rmyl-3-Methoxypregrta3,5-Dien-20-One 0 OMe MeO CHO

17oz acetoxy-3-methoxypregna-3,S-dien-ZO-one (M.P. 175 to 180 C., [a] 147 (c., 1.0 in dioxan) prepared from flea-acetoxyprogesterone and trimethylorthoformate in dioxan, with sulphuric acid as catalyst, and purified from acetone/hexane or chloroform/ethanol +1% pyridine) (18.5 g.), in ethylenedichloride (150 ml.) was added to the complex prepared at 0 C. from dimethylformarnide (18 ml.) in ethylene dichloride (65 ml.) and phosgene (12.5 g.) in ethylenedichloride ml), and the mixture was stirred and allowed to warm to room temperature over 3 hours. The resulting complex was hydrolysed in aqueous methanol ml., 90%) containing sodium acetate (25 g.) for 10 minutes. The product was extracted with ether which was washed with sodium carbonate solution and water, dried (sodium sulphate), decolourised (charcoal) and the solvent removed. The 6-formyl derivative, purified from acetone/ hexane, followed by ethanol, formed prisms, MP. 218 to 223 C., [0:1 --158 (0., 1.06 in CHClg);

A222? 219 to 220 ni (6 10,570) and 321 my (6 15,380); m (in CI-I Cl 1729, 1714, 1651, 1612 and 1581 cm.-

EXAMPLE 13 Preparation of 21-Acet0xy-3-Eth0xy-6-F0rmyl-1 7a- Hydroxypregna-3,5-Diene-11,20-Dione Cortisone acetate 3-enol ethyl ether (5 g.) in ethylenedichloride (160 ml.) containing a drop of pyridine was added to the complex prepared at 0 C. from dimethylformamide (5.5 ml.) in ethylenedichloride (20 ml.) and phosgene (3.6 g.) in ethylenedichloride (35 ml.) After stirring for 2 hours, while the mixture was allowed to warm to room temperature, an orange-red precipitate had formed. The mixture was poured into methanol (100 ml.) containing sodium acetate (10 g.) and stirred for /2 hour, then ether and water were added, and the ether was washed with water, sodium hydrogen carbonate solution, and water, the washings being re-extracted with ether.

The combined ethereal solutions were dried (sodium O OMe Moo- 16a,17ot-epoxy-16fi-methylprogesterone g.), dioxan (50 ml.) and methylorthoformate (5 ml.) were treated with p-toluenesulphonic acid (150 mg.) and allowed to stand for 1 hour at room temperature. Pyridine (0.5 ml.) was then added and the solution poured into ice-water. Filtration and crystallisation of the resulting solid from methylene chloride/methanol gave 3-methoxy-l6a,17aepoxy-16fi-methylpregna-3,5-diene 20-0ne, M.P. 128 to 130 C., [(11 71 (CHClg).

To a suspension of the phosgene/dimethylformamide complex prepared trom dimethylformamide (3.2 g.; 0.044 M) and phosgene (2.18 g.; 0.022 M) in ethylenedichloride (15 ml.) was added a solution of the foregoing enol ether (3.56 -g.; 0.01 M) in ethylenedichloride (20 ml.) at 0 C. and the reaction mixture was then allowed to warm to room temperature. After 1 hour a solution of anhydrous sodium acetate (6 g.) in water ml.) and methanol (40 ml.) was added and the mixture stirred for a further minutes. More water was added and the product isolated with ether. Crystallisation from acetone/hexane gave '3- methoxy-17a-hydroxy-6-forrnyl-16-methylenepregna 3,5- diene-ZO-one, M.P. 199 to 201 C., [1x1 276 C.

EXAMPLE 15 Preparation of 1 7fi-A cetoxy-o-Formy l-3-Meth oxyandr0sta-3,5-Diene The use of phosphorus pentachloride in the preparation of 6-formyl derivatives is illustrated by the following:

To a solution of dimethylformamide (3.18 g.; 3.3 ml.) in ethylenedichloride (12 ml.) was added slowly, with stirring, at 0 C. a suspension of phosphorus pentachloride (4.0 g.) in ethylenedichloride (40 ml). When the addition was complete (ca. 10 minutes), the reaction mixture was stirred :for a further ten minutes and then a slurry of the 3-methyl enol ether of testosterone acetate (2.6 g.) was added in ethylenedichloride (8 ml.). A red colour slowly developed. The reaction mixture was stirred for three hours and then hydrolysed by a solution of sodium acetate (4.5 g.) in water (8 ml.) and methanol (35 ml). The mixture was stirred for ten minutes and then more water was added. The organic material was extracted with ether, the ether washed with water, dilute sodium bicarbonate solution and then Water, and dried over calcium chloride. The solvents were removed and the residue triturated with methanol to give the 6-formyl derivative, M.P. 160 to 163 C., after crystallisation from acetone/hexane. The M.P. was not depressed on admixture with a sample prepared by the process of Example 10.

re EXAMPLE 16 The 3-enol methyl ether of testosterone acetate was converted into the 6-formyl derivative by (a) Treating a suspension of the steroid in ethylenedichloride and dimethylformamide at 0 C. with a solution of phosgene in ethylenedichloride.

(b) Treating a suspension of the steroid in dimethylformamide with phosphorus oxychloride at 0 C.

(c) Using 1.1 mol. proportions of ph'osgene and dimethyl formamide and 1.0 mol. proportions of steroid.

(d) Treating a suspensin of the steroid in dimethylformamide and ethylenedichloride with phosphorus oxychloride at 0 C.

In all cases the mixtures were left at room temperature for 2 to 3 hours and Worked up as in Example 10.

EXAMPLE 17 6-formylation of l7fl-acetoxy3-methoxyandrosta-3,5- diene was carried out according to the process of Example 10, using the following formamides in place of dimethylformarnide:

N,N-diethylforrn amide N-ethyl-N-phenyl-formamide N-formyl-piperidine N-formyl-morpholine In all cases the 6-formyl derivative, M.P. 159 to 161 C., was obtained.

EXAMPLE 18 Preparation of 1 7/3-A cet0xy-3-Benzy l0xy-6-F0rmyl- A ndr0sta-3 ,5 -Diene Phosgene (2.1 g.) in ethylenedichloride (20 ml.) was added drop-wise with stirring to dimethylformamide (2.9 ml.) in ethylenedichloride(10 ml.) at 0 C. A suspension of 17,8-acetoxy-3=benzyloxyandrosta-3,S-diene (8 g.) in ethylenediehloride (50 ml.) and pyridine (0.1 ml.) was added, and the mixture was stirred and allowed to warm to room temperature over 1 hour. Sodium acetate (5 g.) in methanol (50 ml.) was added, the mixture was stirred for a further 10 minutes, then water and ether were added. The organic solvents were washed with water and sodium bicarbonate solution, dried (sodium sulphate), stirred with charcoal, and the solvents removed. Purification of the solid residue from methylene chloride/ methanol gave the 6-formyl derivative as needles, M.P. 199 to 201 C., [@1 3 143 (0., 1.1 8 in CHCl M33? 322 ma (6 16,285)

EXAMPLE 19 Preparation of l 7a-Acet0xy-16-Ethylidene-fi-Formyl-3- M eth0xypregna-3,5 -Dien-20-One I OAc i ]=CH.CH3 hlle CHO 17a acetoxy 16 ethylidene 3 methoxypregna- 3,5-dien-20-one [0.58 g., M.P. 205 to 208 C., [a],; 231 (c., 0.7 in CHCI prepared from the corresponding 4-en-3-one by treatment with methyl orthoformate in dioxan containing a trace of sulphuric acid] in dry ethylenedichloride (2 ml.) containing a trace of pyridine was added at 0 C. to a stirred suspension of the complex prepared from dimethylformamide (0.8 ml.) and phosgene (0.3 g.) in dry ethylenedichloride (6 ml.). After warming to room temperature over 2 hours the mixture was worked-up as in Example 8. 17a-acetoxy 16 ethylidene 6 formyl 3 methoxypregna 3,5- dien-ZO-one formed prisms from dichloromethane/methanol, M.P. 203 to 204 C., -255 (c., 0.7 in CHC1 A523? 213 In (flat) (6 11,750) and 320 m (6 15,290) EXAMPLE 20 Preparation of 3-Ethyl-Enol Ether f 6-Formylpregna- 4,17(20) -Dien-3-One-21-Oate Ethyl Ester CHO A solution of phosgene (1.45 g.) in ethylenedichloride (12 ml.) was added dropwise, during minutes, to a stirred solution of dimethylformamide (2.2 ml.) in ethylenedichloride (8 ml.) at 0 C. Wtih exclusion of moisture. After a further minutes, stirring, a solution of 1.92 g. of 3-ethyl-enol ether of pregna-4,17(20)- dien-3-one-21-oate ethyl ester (prepared by the method of Patel, Petrow, Royer and Stuart-Webb, J. Chem. Soc., 1952, 161) in ml. of ethylenedichloride, containing a few drops of pyridine, was added, and the mixture was stirred at room temperature for 2% hours. A solution of 3 g. of sodium acetate in 5 ml. of water and ml. of methanol was added, and after 10 minutes stirring, the mixture was diluted with water and extracted with ether, dried over sodium sulphate, treated with charcoal, and stripped. The resulting solid was recrystallised from ethanol as pale yellow crystals x 222 to 223 ma (6 26,565) and 323 m (a 14,750) (in ethanol) 7mm (in CCl 1715, 1662 and 1619 cmf EXAMPLE 21 Preparation of 6-Formyl Derivative of Testosterone Acetate 3-Methyl Enol Ether To a solution of 3.3 ml. (3.15 g.) dimethylformamide in 12 ml. of dry methylenedichloride was added, slowly with stirring at 0 C. a 12% w./v. solution of phosgene in ethylenedichloride (18.5 ml.). When the addition was complete, the mixture was stirred for ten minutes, a complex separating out. At the end of this time a slurry of 3.0 g. testosterone acetate 3-methyl enol ether in 8 ml. of methylenedichloride was added when the reaction mixture turned a reddish brown. It was warmed to 50 C. (bath temperature) and thus maintained for one hour. Working up as described in Example 10 yielded the 6-formyl derivative identical with a sample prepared in Example 10.

EXAMPLE 22 Preparation of 21 -Acetoxy-6-Formyl-1 7u-Hydr0xy-3-(2 H ydroxyelhoxy -Pregna-3,5 -Diene-l 1,20-Di0rre The formylating reagent was prepared from dimethylformarnide (5.5 ml.) in ethylenedichloride (20 ml.) and phosgene (3.6 g.) in ethylenedichloride (35 ml.) at 0 to 5 C. Cortisone acetate 3-ethylene ketal (5 g.) suspended in ethylenedichloride (50 ml.) was added, and the mixture stirred and allowed to warm to 30 C. over 4 hours. Sodium acetate (6 g.) in methanol (60 ml.) was then added, and the mixture stirred for 60 minutes. Ether and Water were added, and the organic layer was washed with water and sodium bicarbonate solution, dried (sodium sulphate), stirred with charcoal, filtered, and the solvent removed under reduced pressure to give 21 acetoxy 6 formyl 17a hydroxy 3 (2' hy- EXAMPLE 23 Preparation of 3 -Ethoxy-6 -F0rmyl-1 7,8-Propionoxy- 1 7 a- (Prop-1 '-Ynyl A ndrosta-3,5-Dl'ene A solution of 17,6-hydroxy-17a-(prop 1'-ynyl)-androst- 4-en-3-one (Barton, Burn, Cooley, Ellis and Petrow, J. Chem. Soc., 1959, 1957) (5 g.) in propionic anhydride (25 ml.) and pyridine (25 ml.) was boiled under reflux for 4 hours, cooled and poured into water. The precipitated solid was recrystallised from aqueous methanol to give 17fl-propionoxy-17a-prop-1-ynyl)androst- 4-en-3-one as laths, M.P. 128 to 129 C. [M +9 (c., 1.0 in chloroform).

A solution of the foregoing compound (3.75 g.) in dry dioxan (20 ml.) and ethyl orthoformate (2 ml.) was treated with a solution of concentrated sulphuric acid (2 drops) in dry dioxan (5 ml.) and left at room temperature for 30 minutes. Pyridine (5 ml.) was added and the mixture poured into water (200 ml.) to give a gum, which was isolated with ether and crystallised from aqueous methanol (containing a trace of pyridine) to give 3 ethoxy 17B propionoxy 17a (prop 1- ynyl)androsta-3,5-diene, small needles, M.P. 106 to 107 C., -192 (c., 1.03 in chloroform).

The foregoing compound (2 g.) was added to a stirred, ice-cooled suspension of the formylating reagent [prepared by the addition of a solution of phosgene in ethylenedichloride (7 ml., 12%) to a solution of dimethylformamide (1.1 ml.) in ethylenedichloride (10 ml.)] containing a trace of pyridine. The mixture was stirred at room temperature for 1 hour, when a solution of sodium acetate (3 g.) in water (5 ml.) and methanol (20 ml.) was added, and the mixture stirred. for a further 10 minutes. Water ml.) was added and the product isolated with ether to give 3-ethoxy-6-formyl- 17,6 propionoxy 17a (prop 1' ynyl)androsta 3,5- diene,

E1? 1730, 1650, 1620 and 1580 cm.-

EXAMPLE 24 Preparation of 21 Acetoxy-l7a-Hydr0xy-3-Meth0xy-6- Formylpregna-3,5,9(11 )-Trien-20-One CHzOAc MeO- CHO

19 product was precipitated into water (2 litre-s), and purified from aqueous methanol to give needles, M.P. 158 to 166 C., [aJ -84 (c., 0.89 in dioxan), k 240 to 241 ma (6 19,700).

(b) 21 =acetoxy-17a-hydroxy-3-methoxypregna 3,5, 9(11)-trien-20-one prepared as described above (8 g.) was dissolved in ethylenedichloride (80 ml.) containing a drop of pyridine and the solution added to the reagent prepared at C. from dimethyl formamide (6 ml.) in ethylenedichloride (30 ml.) and phosgene (3.5 g.) in ethylenedichloride (35 ml.). After stirring for 1 hour sodium acetate (6 g.) in methanol (80 ml.) was added, and stirring continued for 10 minutes. The product [isolated as in Example 13] was purified from aqueous methanol to give the 61fonmyl derivative, soft needles, M.P. 180 to 184 C., [04],; -95 (c., 1.42 in chloroform), hmax. 219 10 220 my. (6 12,100) and 322 111,11. (6 15,400).

EXAMPLE 25 Preparation of 3-Methoxy-6-F0rmyl-J 704,21 M ethoxymethyl ened ioxypregna-3,5 -Diene-1 1 ,20-Di0ne 3-methoxy 1706,21 methoxymethylenedioxypregna- 3,5-diene-11,20-dione was prepared from cortisone (10 g), trimethyl orth-oformate (20 m1.), toluene-p-sulphonic acid (0.5 g.) and benzene (400 ml.), by slow distillation of the solution for /2 hour, addition of pyridine ml.), Washing with water, evaporaton of the solvent, and purification from ethanol. It was obtained as prisms, M.P. 147 to 152 C., 3 1 (c., 0.51 in CHC-l The last compound (1 g.) in ethylenedichloride (20 ml.) was added to the complex prepared at 0 C. from phosgene (0.3 g.) in ethylenedichloride (3 ml.) and dimethylformarnide (0.8 ml.) in ethylenedichloride (5 ml.). After stirring for 1 hour at room temperature sodium acetate (1 g.) in methanol (20 ml.) was added and stirring continued for minutes. Ether and water were added, and the organic layer was washed, dried (sodium sulphate) and the solvents removed. Purification from aqueous methanol gave the 6-formyl derivative as needles, M.P. 185 to 190 C., A 219 In (6 11,560) and 322 'mu (6 14,050), of the following structure 17 3 hydroxy-3-methoxyandrosta-3,S-diene was prepared by hydrolysis of the corresponding 17fi-a'cetoxy derivative with potassium hydroxide in methanol followed by purification from aqueous methanol. It formed flakes, M.P. 125 to 127 C., [a] 128 (c., 0.93 in dioxan),

AELOH 240 Inn (6 17,540)

It was treated with 2.5 equivalents of the formylating reagent to give the 17-formoxy-6-formyl derivative, which, on prolonged boiling with methanol afforded 17fl-hydroxy-3-methoxy-6-formylandrosta-3,S-diene, polyhedral crystals, M.P. 105 to 110 C., [04],; 144 (c., 1.28 in chloroform), 7\,,,,,,, 220 ma (6 10,050) and 322 my. (e 15,100).

20 EXAMPLE 27 Preparation of 1 7 ,8-A cetoxy-I 7a-Methyl-3-Meth0xy-6- Formylandrosta-3,5-Diene (a) Sulphuric acid (0.12 ml.) was added to a solution of 17u-methyltestosterone acetate (Miescher and Klarer, Helv. Chim. Acta, 1939, 22, 962) (10 g.) in a mixture of dry dioxan rn1.), methyl orthoformate After 25 minutes at room temperature, pyridine (0.6 ml.) was added followed by a large volume (ca. 1 1.) of water. The aqueous supernatant was decanted off and the residual gum crystallised from methanol containing a trace of pyridine to give 3-enol methyl ether, fiat needles, M.P. 112 to 114 C., [M -141 (c., 0.87 in chloroform) k 240 ma (6 18,785)

(b) A stirred mixture of dimethylformarnide (8.5 ml.) and ethylenedichloride (30 m1.) at 0 C. was treated with phosgene (5.5 g.) in ethylenedichloride ('55 m1.) added dropwise over 15 minutes. Ten minutes later, a solution of the foregoing enol ether (7.5 g.) in ethylenedichloride (37.5 ml.) was added, and the mixture stirred at room temperature for 2 hours. After hydrolysis with aqueous methanol/sodium acetate, the product was isolated with ether and purified from methanol. 17/3-acetoxy 6 formyl-3-methoxy 17ot-methylandrosta-3,5-. diene formed prisms, M.P. 118 to 123 C., 141

(0., 0.84 in dioxan) A 220 my. (e 10,550) and 322 1111!.(6 15,690), 23,? 1740,

max.

EXAMPLE 28 Preparation of 6-F0rmyl-3-Meth0xy-21-Methylpregna- 3,5-Dien-20-One 21-methylprogesterone (Helv. Chim. Acta, 1940, 23, 1371) (10 gms.) was dissolved in dioxan (50 ml.) and mixed with methylorthoformate (11 ml), methyl alcohol (0.5 m1.) and toluene-p-sulphonic acid (1.0 g.) and left for 30 minutes at room temperature. Pyridine (3 ml.) was added to the mixture and the product was precipitated by the addition of water. The solids were collected and crystallised from methanol containing a few drops of pyridine to give 3-methoxy-21-methylpregna- 3,5-dien-20-one as needles.

Phosgene dissolved in ethylenedichloride (40' mls. of a 10% w./v. solution) was added dropwise to a stirred solution of dimethylformamide (6.1 ml.) in ethylenedichloride (20 mls.) cooled in an ice bath. 3-methoxy- 21-methy1pregna-3,5-dien-20-one 10 g.) in ethylenedichloride (30* ml.) was added and the reaction mixture was stirred and the cooling bath was removed. After two hours, the mixture was poured into aqueous methanolic sodium acetate solution and the product isolated with ether. 6-formy1-3-methoxy-21-methylpregna-3,5- dien-20-one was obtained as an amorphous solid;

A212 219 to 221 Inn and 318 to 321 mu EXAMPLE 29 Preparation 0 f 3 -eth0xy-6-F army l-] 7 fi-Propionoxy- 17a-Vinylandr0sta-3,5-Diene OCOEt EtO (a) A solution of 17a-vinyltestosterone (5 g.) in propionic anhydride (25 m1.) and pyridine (25 ml.) W218 boiled under reflux for 4 hours, cooled and poured into water. The precipitated solids were recrystallised from aqueous methanol to give 17/3-propionoxy-17a-vinylandrost-4-en-3-one as needles, M.P. 126 to 127 C., +104 (c., 1.06 in chloroform).

A solution of the foregoing compound (4.15 g.) in dry dioxan (25 ml.) and ethyl orthofromate (2.5 ml.) was treated with a solution of concentrated sulphuric acid (3 .drops) in dry dioxan (3 ml.) and the mixture left at room temperature for 30 minutes. Pyridine (2 ml.) was added and the mixture diluted with water. The precipitated oil was isolated with ether and crystallised from methanol (containing a trace of pyridine) to give 3-ethoxy-17fi-propionoxy 17cc vinylandrosta-3,5-diene, small needles, M.P. 103 to 104 C., [(11 96 (c. 0.95 in chloroform).

The foregoing compound (2 g.) was added to a stirred ice-cooled suspension of the formylating reagent [prepared by the addition of a solution of phosgene in ethylenedichloride 7 ml.) to a solution of dimethylformamide (1.5 ml.) in ethylenedichloride (8 ml.)] containing a trace of pyridine. The mixture was stirred at room temperature for 1 hour, then stirred for 10 minutes with a solution of sodium acetate (3 g.) in water (5 ml.) and methanol ml.). Water (100 ml.) was added, and the product isolated with ether, to give 3- ethoxy-6-formyl-17fi-propionoxy 17cc vinylandrosta- 3,5-diene as a gum,

7m, 1730, 1650, 1620 and 1580 cmf EXAMPLE 30 Preparation of the o-Formyl Derivative of Testosterone Acetate 3-En0l Methyl Ether Phosgene (2 g.) in ethylenedichloride (17 ml.) was added to a suspension of testostreone acetate 3-enol methyl ether (3.44 g.) in 20 ml. ethylenedichloride and dimethylformamide (5 ml.) and the mixture stirred for 2% hours at room temperature. On isolating the product by the method of Example 10, the 6-formyl derivative was obtained.

EXAMPLE 31 Preparation of ZOB-Acetoxy-3-Ethoxy-6-Formylpregna- 3,5-Diene EtO CHO

(a) A solution of 2OB-acetoxy-3-ethoxypregna-3,5- diene [6 g. M.P. 126 to 129 C., [(11 -80.6 (c., 1.08 in dioxan),

max.

22 needles, M.P. to 189 C., [04],; 6l (c., 0.97 in chloroform) A232? 222 to 223 my (6 10,820) and 322 m (6 13,520)

EXAMPLE 32 Preparation of 1 7 uc-A cet0xy-6 -F ormy l-3 -M ethoxy-l 6 a- Met/1ylpregna-3,5-dien-20-0ne 17a-acetoxy-16oc-methylpregn-4-ene-3,20-dione (British patent application No. 29,378/60) (3 g.) was dissolved in dioxan (18 ml.) and treated with methyl orthoformate (3.2 ml.), methanol (0.1 ml.) and toluene-p-sulphonic acid (0.3 g.) for 30 minutes at room temperature. The product was precipitated by the addition of pyridine and water and crystallised from methanol containing a few drops of pyridine to give 17a-acetoxy-3-methoxy-16amethylpregna-3,5-dien-20-one, plates, M.P. 198 to 200 max.

1222? 220 m and 321 III/1 EXAMPLE 33 Preparation of 6-F0rmyl-20-Hydr0xy-3-Meth0xypregncz- 3,5-D1'en-]8Oic Acid (1820) Lactane Ody Me (\I CH O A solution of 20-hydroxy-3-oxopregn-4-en-18-oic acid (18 20) lactone (Labler and Sorm, Chem. and Ind., 1960, 935) (1 g.) trimethylorthoformate (2.5 ml.), methanol (0.1 ml.) and toluene-p-sulphonic acid (0.1 g.) in dry dioxan (25 ml.) was kept at room temperature for 6. hour. Excess acid was neutralised by the addition of pyridine and the mixture was poured into water. The precipitated solid, 20-hydroxy-3-methoxypregna-3,5- dien-18-oic acid (18 20) lactone was collected and dried over P 0 It showed MeO- :31? 1750, 1660, and 1627 cm."

A solution of the foregoing enol ether (1 g.) in dry ethylenedichloride (10 ml.) was added at 0 C. to a stirred suspension of the complex prepared from dimethylformamide (1.1 ml.) and phosgene (0.75 g.) in dry ethylenedichloride (10 ml.) and the mixture was allowed to warm to room temperature over 2 hours. After hydrolysis with aqueous sodium acetate, the product was isolated with ether. Purification by chromatography afforded 6-formyl-20-hydroxy-3-methoxypregna-3,5-dien- 18-oic acid (18920) lactone, having Nuio 7m 1752, 1660, 1620, and 1580 cmf 23 EXAMPLE 34 6 -Frmyl-C0rtisone-1 701,2] -Dz'acetate-3 -M ethyl Enol Ether CHO (a) Cortisone-I7u,21-diacetate-3-meflhyl enol ether.- Cortisone-17u,21-diacetate (5.7 g.) was dissolved in dioxan1(45 m1.) and trirnethyl orthoformate (7 1111.), and concentrated sulphuric acid drops) added to the stirred solution. After stirring for 20 minutes, the acid was neutralised with pyridine, and the solution diluted with water. Filtration, and recrystallisation from moist metha nol containing a trace of pyridine gave the enol ether, MP. 160 to 163 (3., [M 60 (c., 0.888 in dioxan). (b) A solution of cortisone-17a,2l-diacetate-3-methyl enol ether (5.4 g.) in ethylenedichloride (40 m1. containing a trace of pyridine) was added to the reagent prepared from dimethylformamide (8.5 ml. in 20 ml. ethylenedichloride) and phosgene (20 m1. of a w./v. solution in ethylenedichloride). After stirring for 4 hours, the mixture was poured into methanol (60 ml.) containing water (16 ml.) and sodium acetate (10.0 g.), shaken and extracted with methylene chloride. The extracts were combined, washed with water, dried and evaporated, and the residue recrystallised from moist methanol to give the product, MP. 198 to 200 C. raised to 203 to 206 C., 73.7 (0., 0.963 in CHCl after further purification from methanol.

EXAMPLE 35 MOO- CHO

To a solution of dimethylformamide (1.5 g.) in dry ethylenedichloride (6 ml.) at 0 C. was added, slowly, with stirring, a solution of phosgene in ethylenedichloride (10% w./v.: 10.5 ml.). After a further 10 minutes, a solution of 3-methoxy-17B-acetoxy-oestra-2,5(10)-diene 1.5 g.) (US. Patent 2,846,452) in ethylenedichloride (7.5 ml.) was added, and the mixture was allowed to warm to room temperature and stirred for a further 3 hours. A solution of sodium acetate (1.5 g.) in water (1.5 ml.) and methanol ml.) was added, and, after 10 minutes, the mixture was extracted with ether. The ether solution was washed with sodium bicarbonate solution and with water, dried over sodium sulphate and evaporated to dryness. The resulting oil solidified on trituration with methanol. Recrystallisation from meth- 24 anol yielded 6-formyl-3-methoxy-17B-acetoxy-19-nor androsta-3,5-diene, k 219 m 321 mp,

735,? 1731, 1651 and 1608 emr ,9,5;

max.

EtO-

CHO

To a solution of dimethylformamide (3.3 ml.) in dry ethylenedichloride (12 ml.) at 0 C., was added, slowly,

with stirring, a solution of phosgene in ethylenedichloride (10% w./v.; 22 ml.). After a further 10 minutes, a solution of 19-nor-testosterone acetate 3-ethyl enol ether (A. Ercoli and R. Gardi, J. Amer. Chem. Soc., 1960, 82, 746) (3.0 g.) in ethylenedichloride (20 ml.) was added and the mixture was allowed to warm to room temperature and stirred for a further 3 hours. A solution of sodium acetate (4.5 g.) in water (7.5 ml.) and methanol (30 ml.) was added, and, after 10 minutes the mixture was extracted with ether. The ether solution was washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated to give 6-formyl-3- ethoxy-17B-acetoxy-19-nor-androsta-3,5-diene as a gum, k 216 to 221 my. and 320 mp,

ygg 1730, 1651, 1609 Cm. ,25; 1242, 1212, 1191,

1322, 1294 cmr EXAMPLE 37 21 -Benzylidene-3-Eth0xy-6-Formyl-16a,] 7a-Is0pr0- pylidenedioxypregna-3,5-Dien-ZO-One 3 ethoxy 1607,1711 isopropylidenedioxypregna 3,5- dien-ZO-one (2.0 g.) (prepared as described in Example 1) suspended in ethanol (20 ml.) was treated with benzaldehyde (1 ml.) followed by a solution of sodium (1 g.) in ethanol (40 ml.). The mixture was heated under reflux for 15 minutes during which time the steroid passed into solution. Water was added and the precipitated solid purified from aqueous ethanol containing a trace of pyridine to give 2l-benzylidene-3-ethoxy-16oz,17misopropylidenedioxypregna 3,5 dien 20 one as yellow plates, M.P. 183 to C. dec., -75 (c., 1.01 in dioxan), A 230 (6 24,330), 240 (6 20,760) and 297.5 mu (6 23,577),

7E3? 1675, 1650, 1620, 1590 and 1560 cm.

The foregoing compound (3.14 g.) in ethylenedichloride (15 ml.) was added to the formylation mixture prepared frorn phosgene (22 ml. of 10% solution in ethylenedichloride) and dimethylformamide (3.15 g.) in ethylenedichloride (13 ml.). After being stirred for 2 hours the mixture was poured into a solution of sodium acetate (4.5 g.) in water (7.5 ml.) and methanol (30 ml.). After being stirred for 10 minutes, water was added and the product isolated with ether. The brown gum obtained after removal of the solvents in vacuo was chromatographed on alumina. The fractions eluted with benzene containing 20% ether were purified from ethanol to give 21-benzylidene-3-ethoxy-6-formyl-16a,l7oz-isopropylidenedioxypregna-3,5-dien-20-one, needles, M.P. 161 to 165 C., A 223 to 224 (e 18,790) and 298 my. (6 23,190),

5 K 1719, 1675, 1603, and 1575 cm.-

EXAMPLE 38 17,8-Acetoxy-6-F0rmy[-3-Methoxyandr0sta-3,5-Diene To a stirred solution of 4 ml. dimethylformamide in 16 ml. of ethylenedichloride was added, over 30 minutes at C., 3.72 g. (5.6 ml.) of oxalyl chloride. When the addition was completed, the reaction mixture was stirred for a further ten minutes and then a solution of 4.0 g. testosterone acetate 3-methyl enol ether in 20 ml. of ethylenedichloride was added and the mixture stirred at room temperature for two hours.

At the end of this time, the reaction mixture was poured into a solution of 6.0 g. anhydrous sodium acetate in 10 ml. of water and 40 ml. of methanol and stirred for 30 minutes. Water was then added and the organic constituent extracted with ether, the ether solution washed with aqueous 10% sodium bicarbonate solution until alkaline and then with water until neutral, dried over sodium sulphate and evaporated. The dark gum so obtained was dissolved in ether and the solution run through a short column of alumina (50 g.). The first fraction (from the first 250 ml. of eluent) yielded a sticky solid on evaporation. Purification from acetone/hexane gave the 6-formyl derivative, identical with the material obtained in Example 10.

EXAMPLE 39 1 7 Ct-Cll lorethyny l-l 7,8-F0rm0xy-6-F0rmyl-3-Meth0xyandrosta-3,5-Dielze OOHO A solution of 17a-ch10rethyny1 testosterone (prepared as described in our co-pending British patent application No. 27,179/60) (1 g.) in dry dioxan (15 ml.), methanol (1 ml.) and methyl orthoformate, was treated with 3 drops of concentrated sulphuric acid, and the mixture set aside at room temperature for 40 minutes. The product was isolated with ether and crystallised from aqueous methanol containing a trace of pyridine to give 17u-chlorethynyl-l7fi-hydroxy-3-methoxyandrosta-3,S-diene, plates, M.P. 87 to 90 C., -220 (c., 0.96 in chloroform), A 240 m (log 6 4.26).

The foregoing compound (2 g.) was added to a stirred, ice-cooled suspension of the formylating reagent [prepared by the addition of a solution of phosgene in ethylenedichloride (12 ml. of 10%) to a solution of dimethylformamide (2.1 ml.) in ethylenedichloride (10 ml.)] containing a trace of pyridine. The mixture was stirred at room temperature for 1 /2 hours, when a solution of sodium acetate (3 g.) in water (5 ml.) and methanol (20 ml.) was added, and the mixture stirred for a further minutes. Water (100 ml.) was added and the product isolated with ether to give 17 a-chlorethynyL17fi-formoxy- 6-formyl-3-methoxyandrosta-3,S-diene 1 1740, 1660, 1620 and 1580 cmf 26 EXAMPLE 40 O OMe MeO- CHO

A solution of 'l6ot-cyanoprogesterone (Mazur and Cella, Tetrahedron, 1959, 7, (1 g.) in dry dioxan (15 ml.), methanol (1 ml.) and methyl orthoformate (1 ml.) was treated with 2 drops of concentrated sulphuric acid, and the mixture set aside for 30 minutes. Pyridine (1 ml.) was added, followed by water (60 ml.), and the precipitated solid filtered off and purified from aqueous methanol. 16a-cyano-3-methoxypregna-3,5-dien- 20-one separated in needles, M.P. 167 to 169 C., 69 (c., 1.08 in chloroform), k 240 m (log 6 4.27).

The foregoing compound (1 g.) was added to a stirred ice-cooled suspension of the formylating reagent [prepared by the addition of a solution of phosgene in ethylenedichloride (6 ml. of 10%) to a solution of dimethylformamide (1 ml.) in ethylenedichloride (8 ml.)] containing a trace of pyridine. The mixture was stirred at room temperature for 1 hours, when a solution of sodium acetate (3 g.) in water (5 ml.) and methanol (20 ml.) was added, and the mixture stirred for a further 10 minutes. Water (60 ml.) was added and the product isolated with ether to give 16ot-cyano-6-formyl-3-methoxypregna-3,5-dien-20-one 1730, 1660, 1625 and 1580 cm.

EXAMPLE 41 21 -A cet0xy-6-F0rmyl-1 1 B-Formy loxy-I 7 a-Hydroxy- 3 -M eth0xypregna-3,5 -Dien-20-One Nuiol 'Ymux.

CHzOAc I CHO OCHO Hydrocortisone 21 acetate 11B formate (J.A.C.S., 1955, 77, 3564) (25 g.) in [Analar] dioxan (500 ml.) was treated with methyl orthoformate (25 ml.) and toluene-p-sulphonic acid (2.5 g.) for 45 minutes at room temperature. Excess pyridine was added and the product isolated with ether. Crystallisation from methanol containing pyridine gave 21-acetoxy-llfi-formyloxy-Uu-hydroxy-3-methoxypregna-3,S-dien-ZO-one, M.P. to 187 C., [07],; +8 (c., 1.00 in dioxan) Am! 240 my. (e 19,470)

237 methoxypregna-3,5-dien-20-one, M.P. 210 to 212 C., 19 +16 (0., 1.033 in dioxan) A532 218.5 (6 11,010) 323 mu (6 15,000) EXAMPLE 42 OHaO- l CHO 16a,17a cyclomethylenepregn 4 ene 3,20 dione (J.A.C.S., 1951, 73, 2383) (7 g.) in dioxan (35 ml.) was stirred at room temperature with methyl orthoformate (7 ml.) and toluene-p-sulphonic acid (0.7 g.). After 15 minutes the product crystallised out. Pyridine was added and water and the product collected by filtration. Crystallisation from methanol containing pyridine gave 3- methoxy-16a,17u cyclomethylenepregna 3,5 dien 20- one, M.P. 201 to 202 C., [111 24" (c., 1.04 in dioxan) EtOH Mm.

The foregoing enol ether (3.5 g.) was treated in the usual manner with the complex prepared from phosgene (4 g.) and dimethylformamide (5 ml.) in methylenedichloride. The product was a gum and was chromatographed on alumina (150 g.). Elution with benzene gave 6-formyl-3-methoxy-l6a,17a-cyclomethylenepregna- 3,5-dien-20-one, prisms from methanol, M.P. 205 to 207 C., [a] 53 (c., 0.85 in dioxan) 214 to 215 my. (6 12,600), 321 mp. (6 15,400)

EXAMPLE 43 A solution of [3-[3-keto-17fi-hydroxyandrost-4-en-17ayl]-propionic acid lactone (Cella, Brown and Burtner, J. Org. Chem., 1959, 24, 743) (1 g.) in dry dioxan (20 m1.) and ethyl orthoformate (1 ml.) was treated with concentrated sulphuric acid (2 drops) and left at room temperature for 30 minutes. Pyridine (1 ml.) was added, followed by Water (50 ml.), and the precipitate collected. Recrystallisation from methylene chloride-methanol containing a trace of pyridine gave fi-[3-ethoxy-17fl-hydroxyandrosta-3,5-diene-17a-yl]propionic acid lactone as prisms M.P. 174 to 176 C., -17l (c., 1.14 in chloroform EQOH max.

,YNuiol 1760, 1660 and 1630 cm? max.

' 21-Acet0xy-6-F0rmyl-1 7 oc-H ydroxy- M ethoxypregna-3,5-Diene-l 1,20-Di0ne The Vilsmeier reagent was prepared at 0 C. from dimethylformamide (25 ml.) in anhydrous methylene chloride ml.) and phosgene (16 g.) in methylene chloride (160 ml.). Cortisone acetate-3-enol methyl ether (25 g.) in methylene chloride (250 ml.) containing pyridine (0.5 ml.) was added and the mixture stirred for 2 hours, when an orange-red precipitate separated. Sodium acetate (30 g.) in water (100 ml.) and methanol (100 ml.) was added and the mixture stirred for 20 minutes then diluted with water and ether (600 ml.). The organic layer was washed with water until the washings were colourless, dried (Na SO stirred with decolourising charcoal, filtered, and the solvents were removed under reduced pressure. The product, purified from aqueous methanol, was 21acetoxy-6-iormyl-17a-hydroxy-3methoxypregna-3,5-diene-11,20-dione, flakes, M.P. 200 to 204 C., 15 (c., 0.97 in chlorofonn), A 218 (e=10,890) and 322 m (e=-14,980); Wm (in CHgClg) 1750, 1731, 170 5, 1655', 1615 and 1583 cm.-

EXAMPLE 45 6-F0rmyltesl0l0lactone 3-En0l Methyl Ether p/ Me EXAMPLE 46 1 1 0a,] 7 p-Diacetoxy-6 Formyl-3 M ethoxyandrosza- 3,5-Diene 11a,175-diacetoxyandrost-4-en-3-one (Bernstein et al., J. Org. Chem. 1953, 18, 1166) was converted into its 3- enol methyl ether, A 240 mu (e=20,280) in ethanol, by reaction with methyl orthoformate and toluene-p-sulphonic acid in dioxan.

The 6-formylation, by the process of Example 44 gave 110:,175 diacetoxy 6 formyl-3-methoxyandrosta-3,5- diene, prisms from aqueous methanol, MP. 196 to 199 C., [04 231 (c., 1.01 in chloroform, k

. 219.5 (e=10,420) and 319.5 mg (e=14,460) in ethanol,

'y (in CH CI 1727, 1654, 1619 and 1587 cmr Cortisone (15 g.), dimethylformamide (30 ml.), 2,2- dimethoxypropane (120 ml.) and toluene-p-sulphonic acid mg.) were heated together with slow distillation for 6 hours, during which 40 ml. of distillate was collected. The mixture was cooled to 25 to 30 C. and

treated with methyl orthoformate (15 ml.) and methanol ml.) for minutes, then pyridine (2 ml.) was added. The mixture was distilled under reduced pressure to a volume of 45 ml. then water was added until crystallisation began. Purification from ethanol and 1% pyridine gave cortisone 17,21-acetonide 3-enol methyl ether in prisms, M.P. 188 to 196 C., 30.5 (c., 0.83 in dioxan), A 238 m, (s=20,190) in ethanol.

Formylation by the procedure of Example 44 gave the 6-for myl-derivative, needles from methylene chloride/ methanol, M.P. 195 to 199 C., -40 (c., 0.90 in chloroform), A 219 (e=12,830) and 320 m (6 15,- 200) in ethanol, 'y (in CH CI 1719, 1703, 1654, 1613 and 1583 cm.

EXAMPLE 48 2] -A cet0xy-6-F0rmyl-3-Mezh oxypregna- 3,5,17()-Trzen-11-One (ljll'zOAc OH MeO- ( ZHO 21-acetoxy'3-methoxypregna-3,5,17(20) trien-ll-one was prepared from 21-acetoxypregna-4,17(20)-diene-3, 11-dione (Hogg et al., J. Amer. Chem. Soc., 1955, 77, 4436) by reaction with rnethyl orthoformate and toluenep-sulphonic acid in dioxan. The 3-methoxy compound separated from aqueous methanol in needles, M.P. 141 to 145 C., 41 (0., 0.78 in dioxan).

6-formylation by the process of Example 44 gave the 6 formyl-derivative, solvated prisms from aqueous methanol, M.P. 80 to 91 C., [111 107.5 (c., 0.98 in chloroform), k below 220 III/L and 320 m (e=14,- 000).

EXAMPLE 49 1Set-Acet0xy-6-F0rmyl-3-Methoxypregna- 3,5-Dien-20-One EXAMPLE 50 J 7,8-A cetoxy-3-Etlzoxy-6-F0rmylandr0sta-3,5-Diene Testosterone acetate 3-enol ethyl ether treated in the same manner as the methyl enol ether in Example 10, gave 175 acetoxy-3-ethoxy-6-formylandrosta-3,S-diene,

30 prisms from aqueous ethanol, M.P. 101 to 104 C., (c., 0.81 in chloroform), 220 to 221 In, (6 10,710) and 323 mu (e=15,890) in ethanol.

EXAMPLE 51 1 7B-A cet0xy-3- B-Eth oxyeth oxy -6-F orm y Imzdrosta- 3,5 -Diene EtO.CHz.CH2O- V CHO 6-Formyl-16oz,1 7oz-Ep0xy-3-Meth0xypregna- 3,5 -Dien-2 0-One 16a,17a-epoxyprogesterone was treated with methyl orthoformate and toluene-p-sulphonic acid in dioxan to give the 3-enol methyl ether, M.P. 194 to 195 C. from methanol.

The enol ether (20 g.) was added to the complex prepared from dimethylformamide (20 ml.) and phosgene (10 g.) in methylene chloride (200 ml.). After 1 hour sodium acetate (20 g.) in water (200 ml.) was added, the mixture stirred for 20 minutes, ether (400 ml.) added, and the organic layer was washed until the washings were colourless, dried (Na So and the solvents removed at 30 to 35 C. under reduced pressure. Potassium hydroxide (5 g.) in methanol (100 ml.) was added and the mixture stirred for /2 hour to reconvert any 16,17-chlorohydrin into the epoxide, then water and ether were added, the ether layer was washed, dried, and evaporated, and the residue was purified from ethanol to give 6-formyl- 16a,17a epoxy 3 methoxypregna-3,5-dien-20-one in prisms, M.P. 173 to 176 C., [a] --88 (c., 0.93 in dioxan), Amax- 216.5 (e=12,080) and 320 mu (e=15,635) in ethanol.

EXAMPLE 53 3-Benzyl0xy-6-F ormy landrosta-3,5 -Dien 1 7-One C 5115 C I12 0- I CHO 3-benzyloxyandrosta-3,5-dien-17-one [prepared tfrom the 3-ethoxy analogue by distillation with benzyl alcohol, benzene, and toluene-p-sulphonic acid: needles from acetone, M.P. 172 to 176 C., -49 (c., 0.8 in dioxan)] (10 g.) in methylene chloride (50 ml.) treated with the reagent prepared from dimethyl formamide (5 ml.) in methylene chloride (20 ml.) and phosgene (3.5 ml.) in methylene chloride (35 ml). After stirring for 1.5 hours at room temperature potassium bicarbonate (10 g.) in water (100 ml.) was added dropwise with stirring over /2 hour. Ether ml.) was then added and the organic layer was washed, dried (Na SO decolourised with charcoal, and the solvents removed. Purification ll-oxoprogesterone Was converted by treatment with methyl orthoformate and toluene-p-sulphonic acid in dioxan into its 3-enol methyl ether, A 24-0 mu (e=20,200) in ethanol.

Formylation of the enol ether by the process of Example 44 gave the 6-formyl derivative, A 219.5 (e=10,250) and 320.5 m (e=14,140) in ethanol.

EXAMPLE 55 21 -A cetxy-6-F0rmyl-1 1 ,8,1 7oc-Dihydroxy'3- M ethoxy pregna-3,5 -Dien-20-One ([LHzOAe C 0 MeO- CHO

Hydrocortisone acetate (20 g), anhydrous methanol (40 ml.) methyl orthoformate (40 ml.), tetrahydroiuran (200 ml.) and toluene-p-sulphonic acid (0.4 g.) were stirred together at 28 to 30 C. until a clear solution was obtained (1 hour). Pyridine (2 ml.) was added, and the mixture was poured into ether and water. The ether layer was washed and the solvents removed at 100/ 0.5 mm. The residual gum was purified from aqueous methanol+1% pyridine to give hydrocortisone acetate 3-enol methyl ether, prisms, MP. 170 to 180 C. [(11 15 (c., 1.11 in dioxan), A 239.5 m (e=19,540), M 1751, 1731, 1658 and 1630 (in CH CI The enol ether g.) Was added to the reagent prepared at 0 C. by adding phosgene (2.5 g.) in methylene chloride (25 ml.) to dimethylformamide (4 ml.) in methylenechtloride (20 ml.). After stirring for /a hour at 0 C. the solution was poured into water and sodium acetate (5 g.) and stirred for minutes then the product was extracted with ether. The ethanol solution was washed with water dried (Na SO and the solvents removed. The residue, in methylene chloride was chromatographed on silica gel (100 g.). Elution with methylene chloride+2% acetone and crystallisation of the product from acetone/hexane gave 21-acetoxy-6-formyl-11,8,l7u-dihydroxy-3-methoxypregna-3,5-dien-20-one, MP. 206 to 209 C., [a] -|-16 (c., 0.77 in dioxan), k 218 (e=10,630) and 322.5 mu (e=15,()90), 'y 1750, 1718, 1652, 1614 and 1585 cm? (in CH Cl EXAMPLE 56 O H2OAC 9a-fl uorohydrocortisone acetate was converted into its 3-enol methyl ether by treatment With methyl orthoformate and toluene-p-sulphonic acid in diox-an. The enol ether formed fibrous crystals from aqeuous methan'ol+1% pyridine, Amax, 241 mu (e=21,000) in ethanol.

The foregoing :enol :ether (235 mg.) was added to the reagent prepared from dimethylformamide (1 ml.) and phosgene )350 mg.) in methylene chloride 20 ml.), and the mixture stirred for /2 hour. The product isolated by the process of Example 55, was 21-acetoxy-9a-fluoro- 6 formyl 1118,17a dihydroxy 3 methoxypregna- 3,5-dien-20-one, )t 221 (6: 12,170) and 322 mu (e=13,750) in ethanol.

EXAMPLE 57 6 -F ormy l-3 -M Hilary-95,1 0otPregna-3 ,5 -Dien-20-Oize A solution of 9 8,10a-progesterone (1 g.) (Rec. Trav. Chim. 1960, 79, 771), dry dioxan (20 ml.), methyl orthoformate (2 ml.), methanol (0.25 ml.) and 1% toluene-psulphonic acid in dioXa-n 10 ml.) was kept at room temperature for 1 hour. Pyridine (1 ml.) was added, the mixture was poured into dilute aqueous sodium carbonate and the precipitated steroid was extracted into ether. The residue left on evaporation of the ether was 3-methoxy-9fi,10ot-pregna-3,5-dien-20-one having will? 1710, 1660 and 1630 cm? A solution of the above enol ether (1 g.) in dry ethylenedichlloride (10 ml.) was added at 0 C. to a stirred suspension of the complex prepared from dimethylformamide (0.65 g.) and phosgene (0.4 g.) in dry ethylenedichloride (5 m1.) and the mixture was allowed to Warm to room temperature over 3 hours. The product was isolated as in Example 4 and was 6-formyl-3-methoxy- 9 3,10u-pregna-3,5 -dien-20-one having yfi if 1712, 1565 and 1620 cm.

We claim: 1. 3-enol ethers of 6-formyl-3-ox'o-A steroids selected from the group consisting of:

where R is CHO,

R is selected from the group consisting of H and Me,

R is selected from the group consisting of hydrogen, hydroxy, keto and formoxy,

R is selected from the group consisting of H, Me, OH and OAcyl (where the acyl group contains up to 10 carbon atoms),

R is selected from the group consisting of R and F,

R is selected from the group consisting of H, Me, Et, vinyl, ethynyl, propynyl, chlorethynyl and OH,

R is selected from the group consisting of CH CHR, C=CH C CHMe, CH.CH OH, CHCN and CHHal (where Hail is selected from Cl, Br and F),

R is selected from the group consisting of keto, H(OH) and H(OAcyl),

R is selected from the group consisting of H and F,

R is selected from the group consisting of H and Me, and

R represents part of an enol ether moiety; compounds of the Formula V wherein R, R R R and R have the meaning defined above, and R and R together provide .33 a member selected from the group consisting of :0, =CHCH OAc and compounds of the formula Va wherein R, R R R R R and R have the meaning defined above and R and R together form a radical selected from the group consisting of and I torn compounds of the formula Va wherein R, R R R R", R and R have the meaning defined above and wherein R and R together form a member selected from the group consisting of and OHOMe and the 9(11)-dehy-dno derivatives of the compounds de fined above.

2. 21 acetoxy 6 formyl 170a hydroxy 3 -methoXypregna-3,5-diene-11,20-dione.

3. 21 acetoxy llfi-fonnoxy 6 forrnyl 17cc hydroxy-3-methoXypregna-3,5-dien-20-one.

4. 21 acetoxy 11,8 hydroxy 6 formyl 17a hydroxy-3-methoxypregna-3,5dien-20-*one.

5. 170:,21 diacetoxy 6 formyl 3 methoxypregna- 3,5-dien-1 1,20-dione.

6. 21 acetoxy 3 ethoxy 6 formyl 17a hydnoxypregna-3,5-diene-1 1,20-d-ione.

7. 3 methoxy 6 formyl -.17a,21 methoxymethylenedioxypregnaGJ-diene-1 1,20-dione.

8. 6 formylcortisone 17,21 ace-tonide 3 enol methyl ether.

9. 17oc,20,20,21 bismethylenedioxy 3 cthoxy 6- formylpregna-B ,5 -dien-1 1-one.

10. 21 acetoxy .17ot hydroxy 3 methoxy 6- formylpregna-3,5,9( 1 1 -trien-20-one.

11. 21 acetoxy 6 formyl 3 methoxypregna- 3,5,17(20)-trien-1 1-one.

12. 17a acetoxy 21 fluoro 6 formyl 3 -methoXypregna-3,5-dien-20-one.

13. 17cc acetoxy 6 formyl 3 methoxy 160cmethylpregna-S,S-dien-ZO-one.

14. 170: acetoxy 6 formyl 3 methoxy 16- methylenepregn-a-3,S-dien-ZO-one.

15. 1700 acetoxy 6 formyl 3 methoxypregna- 3,5-dien-20-one.

16. 6 formyl 3 methoxy 16%,170: cyolomethylenepregna-3,5-dien-20-one.

17. 3 ethoxy 6 formyl 16oc,l7ot isopropylidenedioXypnegna-3,5-dien-20-one.

18. 17,8 acetoxy 3 methoxy 6 formylandrosta 3, S-diene.

19. 175 acetoxy 3 methoxy 6 formyl 19 norandrosta-3,5-diene.

20. 6*formyltestololactone 3-en0l methyl ether.

21. 6-forrnyl-3-methoxyandrosta-3,5-dien-l7-one.

22. 3-ethoxy-6-formylspirosta-3,5-diene.

23. 21 acetoxy 3 methoxy 6 formylpregna 3, S-dien-ZO-one.

24. 6 formyl 3 methoxypregna 3,5 dien 20- one.

25. ,8 [3 ethoxy 6 formyl 175 hydroxyandrosta- 3,5-dien-17a-yl] propionic acid lactone.

26. A process for converting a 3-enol ether of a 3-oX0- Af -steroid, unsubstituted in positions 4 and 6, into a corresponding 6-formyl derivative, comprising: treating the said 3-enol ether with a Vilsmeier reagent, under anhydrous conditions, to provide a corresponding 6-iminium intermediate, and hydrolyzing said G-iminium intermediate to provide said 6-formyl derivative.

27. A process for converting a B-enol ether of a 3-oXorid-steroid into a corresponding 6-formy1 derivative having in rings A and B the following structure:

where R is selected from the group consisting of O-alkyl, O-hydroxyalkyl, O-cycloalkyl, O-alkaryl, and O-alkoxyalkyl, comprising: treating a corresponding 3-enol ether, unsubstituted in positions 4 and 6, under anhydrous conditions with a Vilsmeier reagent, formed by the reaction of a forrnylated secondary amine and an acid halide with nucleophilic displacement of a halogen ion, to give a corresponding 6-iminium intermediate and subjecting said intermediate to aqueous hydrolysis to decompose the 6 iminium group to a 6-formyl group.

28. A process as claimed in claim 26 wherein the 3-e110l ether steroid starting material is reacted with the Vilsmeier reagent under anhydrous conditions at a temperature not substantially above room temperature and the resulting iminium intermediate is converted into the required formyl derivative by reaction with a reagent selected from the group consisting of aqueous sodium acetate and aqueous methanolic sodium acetate.

29. A process as claimed in claim 26 wherein the Vilsmeier reagent is a complex formed from dimethyl formamide and a compound selected from the group consisting of phosphorus oxychloride and phosgene.

30. A process as claimed in claim 29 wherein a 3-enol ether steroid starting material in ethylene dichloride and dimethylformamide at 0 C. is treated with a solution of phosgene in ethylenedichloride.

31. A process as claimed in claim 30 wherein the 3-enol ether steroid starting material in dimethylformamide with or without ethylenedichloride is treated with phosphorus oxychloride at 0 C.

32. A process as claimed in claim 26 wherein the Vilsmeier reagent is prepared by treating a stirred mixture of dimethylformamide and ethylenedichloride at 0 C. with phosgene in ethylenedichloride with exclusion of moisture.

33. A process as claimed in claim 29 wherein 1.0 molar proportion of the 3-enol ether steroid starting material are employed and at least 1.1 molar proportion of phosgene and dimethylformamide.

No references cited. 

1. 3-ENOL ETHERS OF 6-FORMYL-3-OXO-$4 STEROIDS SELECTED FROM THE GROUP CONSISTING OF: 